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Original Investigation |

Saliva and Plasma Quantitative Polymerase Chain Reaction–Based Detection and Surveillance of Human Papillomavirus–Related Head and Neck Cancer ONLINE FIRST

Sun M. Ahn, MD1; Jason Y. K. Chan, MBBS1; Zhe Zhang, MS2; Hao Wang, PhD2; Zubair Khan, MD1; Justin A. Bishop, MD3; William Westra, MD3; Wayne M. Koch, MD1; Joseph A. Califano, MD1,4
[+] Author Affiliations
1Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland
2Division of Biostatics and Bioinformatics, Johns Hopkins School of Medicine, Baltimore, Maryland
3Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
4Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland
JAMA Otolaryngol Head Neck Surg. Published online July 31, 2014. doi:10.1001/jamaoto.2014.1338
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Importance  Human papillomavirus type 16 (HPV-16) is a major causative factor in oropharyngeal squamous cell carcinoma (OPSCC). The detection of primary OPSCC is often delayed owing to the challenging anatomy of the oropharynx.

Objective  To investigate the feasibility of HPV-16 DNA detection in pretreatment and posttreatment plasma and saliva and its potential role as a marker of prognosis.

Design, Setting, and Participants  This is a retrospective analysis of a prospectively collected cohort. Among a cohort of patients with oropharyngeal and unknown primary squamous cell carcinoma with known HPV-16 tumor status from the Johns Hopkins Medical Institutions and Greater Baltimore Medical Center (from 1999 through 2010), 93 patients were identified with a complete set of pretreatment and posttreatment plasma or saliva samples, of which 81 patients had HPV-16–positive tumors and 12 patients had HPV-16–negative tumors. Real-time quantitative polymerase chain reaction was used to detect HPV-16 E6 and E7 DNA in saliva and plasma samples.

Main Outcomes and Measures  Main outcomes included sensitivity, specificity, negative predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status, as well as the association of posttreatment HPV DNA status with clinical outcomes, including recurrence-free survival and overall survival.

Results  The median follow-up time was 49 months (range, 0.9-181.0 months). The sensitivity, specificity, negative predictive value, and positive predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status were 76%, 100%, 42%, and 100%, respectively. The sensitivities of pretreatment saliva or plasma alone were 52.8% and 67.3%, respectively. In a multivariable analysis, positive posttreatment saliva HPV status was associated with higher risk of recurrence (hazard ratio [HR], 10.7; 95% CI, 2.36-48.50) (P = .002). Overall survival was reduced among those with posttreatment HPV-positive status in saliva (HR, 25.9; 95% CI, 3.23-208.00) (P = .002) and those with HPV-positive status in either saliva or plasma but not among patients with HPV-positive status in plasma alone. The combined saliva and plasma posttreatment HPV-16 DNA status was 90.7% specific and 69.5% sensitive in predicting recurrence within 3 years.

Conclusions and Relevance  Using a combination of pretreatment plasma and saliva can increase the sensitivity of pretreatment HPV-16 status as a tool for screening patients with HPV-16–positive OPSCC. In addition, analysis of HPV-16 DNA in saliva and plasma after primary treatment may allow for early detection of recurrence in patients with HPV-16–positive OPSCC.

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Figure 1.
Layout of Patient Groups by Human Papillomavirus Type 16 Status

A, Saliva pretreatment and posttreatment samples; B, plasma pretreatment and posttreatment samples; and C, combined saliva and plasma pretreatment and posttreatment samples. HPV+ indicates human papillomavirus positive; and HPV−, human papillomavirus negative.

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Figure 2.
Kaplan-Meier Curves for Recurrence-Free Survival and Overall Survival

A, Recurrence-free survival is illustrated among patients with human papillomavirus-positive (HPV+) tumors stratified by posttreatment saliva HPV DNA status. B, Recurrence-free survival is illustrated among patients with HPV+ tumors stratified by posttreatment plasma HPV DNA status. C, Recurrence-free survival is illustrated among patients with HPV+ tumors stratified by both posttreatment saliva and plasma HPV DNA status. D, Overall survival is illustrated among patients with HPV+ tumors stratified by posttreatment saliva HPV DNA status. E, Overall survival is illustrated among patients with HPV+ tumors stratified by posttreatment plasma HPV DNA status. F, Overall survival is illustrated among patients with HPV+ tumors stratified by both posttreatment saliva and plasma HPV DNA status. HPV− indicates human papillomavirus negative.

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